Table of contents
2 Antimicrobial agents use in aquaculture
3 Development and spread of antimicrobial resistance
4 Risk Associated with Antimicrobial Resistant in Fish culture
5 Management and alternative strategies
7 Conflict of Interest
Antimicrobial resistance arises due to the overuse of antimicrobial drugs, most prominently antibiotics and others like antivirals, antifungals, etc. An antibiotic is a substance produced by one microorganism that selectively inhibits the growth of another microorganism and there are different types of it. Its use in aquaculture is accompanied by various factors and increasing use of it has several impacts. As of now, the aquaculture sector is growing rapidly and currently, it accounts for more than half of the fish used for human consumption. Demand for food has been increased since the population of the world is growing rapidly so, dependent on aquaculture to provide a safe, reliable, and economic supply of aquatic food has also increased. This increase in production has been accompanied by the intensive use of antibiotics in the aquaculture industry which is leading to the production of antimicrobial-resistant pathogens. Antibiotics are heavily used in the major aquaculture-producing countries nearly 73% of countries use oxytetracycline, florfenicol, and sulphadiazine, and 55% use amoxicillin, sulfadimethoxine, and enrofloxacin. The antimicrobial resistance bacteria transfers' resistant gene to the next generation and it is capable of transferring to another ecosystem also through horizontal gene transfer. The occurrence of such resistance to antimicrobial agents possess serious threats to animal health as well as to human health as it limits the therapeutic options. Hence, detecting such pathogens in time and continuous supervision could help to detect these AMR pathogens which directly helps to disseminate its development as its excessive use in aquaculture have a potential negative impact not only on animals and human health, it also affects the whole aquatic environment The present review summaries the present status of antimicrobial resistance in fish, development of antimicrobial resistance (AMR) and management strategy to tackle the spread of AMR in fish.
List of tables
1 Reported Quantity of Antimicrobial agents intended for animal use by OIE Region, 2014
2 The number of studies and examined number of different classes of antibiotics in the global lake and its comparison with other countries worldwide
3 Antimicrobial Agents (and Classes) Used in Aquaculture and Their Importance in Human Medicine
Some fish associated zoonotic infections
List of figures
1 Consumption trend of antimicrobial agents in Nepal
2 The percentage distribution of fish pathogens exhibiting antimicrobial resistance
3 The process of antibiotic and ARGs transportation through different media and their possible exposure ways to human health
4 The routes of AMR transmission from one system to another
Antimicrobial resistance is a serious threat to global public health as the number of antimicrobial agents are used for both humans and animals. Additionally, its overuse is occurring in different sectors such as humans, animals and agriculture (Collignon & McEwen, 2019). Antibiotic is the most commonly used antimicrobial agent in the case of aquaculture to treat bacterial diseases. An antibiotic is a chemotherapeutic agent which inhibits the growth of microorganisms, for instance, bacteria, fungi, or protozoa. However, the original definition of an antibiotic was a substance produced by one microorganism that selectively inhibits the growth of another microorganism (Kümmerer, 2009; Rodgers & Furones, 2009). Earlier antibiotics discovered were of natural origin such as penicillin which was developed from fungi and streptomycin from bacteria. And in the present scenario antibiotics are derived through a chemical process, such as the sulfa drugs (e.g. sulfamethoxazole). Over the years, the definition of antibiotic has been expanded to include synthetic and semi-synthetic products. Antibiotics are generally divided into groups by either their chemical structure or mechanism of action. They are a diverse group of chemicals that can be divided into different sub-groups such as ß-lactams, quinolones, tetracyclines, macrolides, sulphonamides, and others. These are complex molecules having different functionalities within the same molecule (Kümmerer, 2009).
Aquaculture is growing at a faster rate in the world, and it plays an important role to fulfill the increasing demand for food fish. The transition from capture fisheries to aquaculture has taken place as a result of increasing demand because the natural stocks have been degraded due to pollution and overfishing (Santos & Ramos, 2018). The human population is increasing rapidly so demand for healthy, nutritious, and fresh food has been increased. To meet increasing demand various techniques are being used in aquaculture for increasing production as it has the potential to generate a healthy, nutritious, and fresh food production system. There are numbers of aquaculture types but all of them have the same aim of producing a higher number of aquatic products and a shift from extensive to intensive farming has occurred. Intensification leads to higher production and nutrient pollution which causes a favorable environment for the development of pathogens (Watts, Schreier, Lanska, & Hale, 2017). To treat the infectious disease of the fish strategies like vaccination and antimicrobial agents are used and antibiotics are one of the most effective management. The use of antimicrobial has been increased in aquaculture which has created a large population of drug-resistant pathogens and this resistant gene is transferred to the next generation in fish pathogens and other aquatic animals which has negative consequences on the effectiveness of antimicrobial resistance (Heuer, Collignon, Karunasagar, & Angulo, 2009; Smith P., 2008). Microorganism has become resistant to the medication used against them and this ability of microorganism is becoming prominent. The antibiotic can inhibit the specific type of bacteria and if it loses its inhibiting properties against the same strain then such a condition is known as antibiotic resistance and bacteria which develop such property is antibiotic resistance bacteria (ARB) (Thapa, Shrestha, & Anal, 2020). Resistance to antimicrobial treatment reduces its effectiveness which leads to increase mortality and expanses on the treatment (Smith & Coast, 2021).
Increment of antimicrobial resistance (AMR) in cultured fish is the concerned topic and the incidence of diseases in fish leads to heavy use of antibiotics and thus resistance of bacteria is increasing along with its population in the aquatic environment. The AMR can be transferred horizontally to clinically important strains of the natural environment, which automatically affects the whole ecosystem. Fish pathogens exhibiting several antibiotic resistances are almost present in every fish and that's why detailed knowledge of the gene transfer system for instance plasmid, transposons, integrons, and gene cassettes are necessary to explore the complexity of antimicrobial resistance in aquaculture. Additionally, regular supervision, detecting resistance bacteria in time, and incorporating proper regulations could terminate the AMR in aquaculture (Preeena, Swaminathan, Kumar, & Singh, 2020). Aquatic environments having resistant bacteria and these could transfer to the human environment by horizontal gene transfer. This possess a potential threat to human health because the numbers of antimicrobial agents use in aquaculture are classified as critically important for human use by World Health Organization. So, such increasing use of antibiotic agents in the area of animal production needs to be disseminated to reduce the risk to animal health as well as human health (Heuer et.al, 2009). Pathogens occurring in fish and shellfish have been studied such as Aeromonas salmonicida, A. hydrophila, A. caviae, A. sobria, E. ictaluri, E. tarda, P. damselae piscicida, Vibrio anguillarum, V. salmonicida, V. ordalii, Flavobacterium psychrophilum, Pseudomonas fluorescens, Streptococcus iniae, Renibacterium salmonicarum, Yersinia ruckeri, and Piscirickettsia salmoni. Among them, antimicrobial resistance is mediated mostly by plasmid and mobile genetic elements (MGE), often conjugative, and with the potential for horizontal gene transfer (HGT). Pathogens such as Edwarsiella, Aeromonas, and Streptococcus, could occur in humans causing antimicrobial resistance to zoonotic diseases (Cabello et al., 2013).
2 Antimicrobial agents use in aquaculture
Intensification of aquaculture to fulfill the increasing demand to fish food has led to favorable conditions for the emergence of fish diseases and other water quality problems. Therefore, a wide range of chemicals is used in aquacultures such as antibiotics, hormones, pesticides, anesthetics, and various pigments, minerals, and vitamins. However, the use of antimicrobial agents varies with different operations and countries (Rodgers & Furones, 2009). The use of an antibiotic is high in the major aquaculture-producing countries nearly 73% of countries use oxytetracycline, florfenicol, and sulphadiazine, and 55% use amoxicillin, sulfadimethoxine, and enrofloxacin (Preeena, Swaminathan, Kumar, & Singh, 2020). In aquaculture, antimicrobial agents are administrated mainly through feed or adding it directly into the water and both methods may result in a huge amount of antimicrobial usages. This results in a strong selective pressure in the animals along with their nearby environments (Heuer, Collignon, Karunasagar, & Angulo, 2009; Carvalho, David, & Silva, 2013). In aquaculture use of antimicrobial is mainly for prophylactic purposes and metaphylactic treatment, and there are no specific antibiotics to be used for aquaculture so certified products developed for others sectors of veterinary medicine are used. Thus, overuse of such drugs leads to the selection of aquatic antimicrobial resistance bacteria (AMRB), which degrade the quality of products. In aquaculture, antimicrobials are administrated to whole populations having sick, healthy, and carrier ones, by a process called metaphylaxis. Therefore, the use of antibiotics in aquaculture is higher than in other animal farming, however, the exact usages of it are not easy to assess as different countries have a different regulation system regarding antimicrobial usages (Santos & Ramos, 2018).
Unlike agriculture and medicinal use in aquaculture antimicrobials products are limited and their market is also small and the use of antimicrobial agents is governed by rules and regulations. For instance, in the USA only 5 drugs have been approved by the US Food and Drug Administration (FDA) for disease treatment (Schnick, 2000). Apart from the rules and regulations of the respective country, its use in aquaculture is determined by various other factors such as pathogens present, the treatment timing, condition of diseased fish, and culture parameters (physical and chemical). The number of antimicrobial agents uses is not possible to assess exactly as only a few countries keep a record of its use (Smith P., 2008). However, the use of antimicrobial in aquaculture generally depends on local regulations, and in some countries like Europe, North America, and Japan, they have strict rules and regulations regarding its use. There only a few antibiotics are allowed to use in aquaculture although, most aquaculture is carried out in developing countries where there is a lack of proper regulations (Watts et al., 2017). The antibiotics authorized for use in aquaculture in European countries are oxytetracycline, florfenicol, sarafloxacin, erythromycin, and sulphonamides (potentiated with trimethoprim or ormetoprim), and in the USA, oxytetracycline, florfenicol, Sulfa/trimethoprim, and sulfadimethoxine/ormetoprim are allowed. Despite strict rules and regulations, many countries are using these agents in high amounts for instance India accounts for 8% of total production and usage which are not regulated whereas in China some banned antimicrobial agents are still in use for production which is being neglected (Santos et al., 2018). The European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) project, published an annual report of veterinary antibiotics used in animals in EU/EEA countries along with Switzerland, showed that sales in Europe fell by 34.6% from 2011-2018 (CVMP, 2021). The World Health Organization had published data regarding the use of antimicrobial agents in animals in 2014 which is shown in the given table.
Table 1: Reported Quantity of Antimicrobial agents intended for animal use by OIE Region, 2014
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Source: Data adapted from World Organization for Animal Health (OIE), 2018
Furthermore, it was concluded that Tetracyclines has the largest share globally among all of the antimicrobial’s usages (37.1%), followed by polypeptides (15.7%), penicillin’s (9.8%), macrolides (8.9%), and aminoglycosides (7.8%) (OIE, 2018).
In the case of Nepal, Tetracycline, enrofloxacin, neomycin-doxycycline, levofloxacin, colistin, and tylosin are the most used antibiotics. Antibiotics such as ampicillin, amoxicillin, ceftriaxone, and gentamicin are used without proper prescription. It was found that about more than 70% of these drugs were acquired from retailers or para-professionals. In Nepal, retailers and distributors don't have adequate knowledge regarding effective dosages and their potential side effects. Furthermore, people use such drugs with their own experience or consulting with neighbors (Acharya & Wilson, 2019).
Fig1: Consumption trend of antimicrobial agent in Nepal (Acharya & Wilson, 2019)
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Most countries in South East Asia are under-developing and developing and thus, it has no proper rules and regulations regarding antimicrobial agents’ usages followed by an increased incidence of AMR development than other countries. Myanmar top the list among the highest user of antimicrobial use in animals followed by Indonesia, Nigeria, Peru, and Vietnam in 2010 (Thapa, Shrestha, & Anal, 2020). In Vietnam, 180 different raw food samples including meat and shellfish were examined and found that were contaminated with Salmonella spp., along with Escherichia coli, which were resistant to 15 different kinds of antibiotics (Van, Moutafis, Istivan, Tran, & Coloe, 2007). In a study conducted by Yang et al., 2018 in China, the presence and distribution of antibiotics and ARGs (Antibiotic Resistance Gene) in global freshwater lakes had been examined to show the pollution of antibiotics and ARGs along with its potential risks to the ecosystem and human health. According to their study numbers of antibiotics such as sulfamethoxazole, sulfamerazine, sulfameter, tetracycline, oxytetracycline, erythromycin, and roxithromycin were present at high concentrations in both lake water and lake sediment.
Table 2: The number of studies and examined number of different classes of antibiotics in the global lake and its comparison with other countries worldwide (Yang et al., 2018)
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2.1 Routes of antimicrobial AGENTS’ administration
1. Injection: It is the most effective and direct approach as antibiotics directly get into the bloodstream. It is only suitable for small numbers of fish or important fish species as it is labor-intensive and difficult to follow in commercial fish farming.
2. Mixed with food: For fish providing antibiotics orally by mixing with food is the most common practice (Watts et al., 2017). The required dose of antibiotic is mixed in feed during production or after production with some binding agents such as fish oil and canola oil. In this method, early detection of suffering fish is needed as only fish-eating feed will be treated. Very sick fish will not eat the feed resulting in mortalities (Yanong, 2016).
3. Bath treatment: It is a popular method for administrating antibiotics. However, it requires a large number of drugs as compared to injection and oral administration to achieve the desired level of result. In bath treatment there is no guarantee that the use of antibiotics in a large quantity will effectively get into fish, a large proportion of it may go into sediment which ultimately degrades the water quality and creates a favorable condition for AMR development. This method should be applied only when the majority of fish are suffering (Yanong, 2016).
3. Development and spread of antimicrobial resistance
The development of antimicrobial resistance and its spread has become a serious issue as it has negative aspects on both animal and human health along with the whole ecosystem. It is said that the use of antimicrobial agents developed antimicrobial resistance microorganisms and it passes the resistance genes to the next generation. The spread of antimicrobial resistance is not necessarily restricted by phylogenetic, geographic, or ecological borders. Thus, the use of antimicrobial agents in one ecological niche, such as in aquaculture, may impact the occurrence of antimicrobial resistance in other ecological niches, including the human environment (FAO, WHO, OIE, 2003). Antibiotics are the primary treatment practice against diseases so it plays an important role in modern medicine. Antibiotic resistance is not a new thing, it is an ancient process and predates any clinical use although, excessive use of it has raised a serious concerned issue of AMR. Bacteria are becoming resistant to several antibiotics because of natural processes and human activities (Levy & Marshall, 2004; Davis & Davies, 2010). Antibiotics are provided to fish either by mixing in feed (mostly) or by injection and bath so this method leads to the high amount of unconsumed (30%) medicated feed that accumulates on the bottom surface. Among ingested about 80% pass into the environment through urination and excretion in unabsorbed form and these contain in sediments are carried to distant via water currents causing its widespread (Cabello et al., 2013).
Bacteria can develop antimicrobial resistance through various processes such as mutation, horizontal gene transfer (HGT), natural transformation, transduction, and conjugation (Iwasaki & Takagi, 2009; Aminov, 2011; Marti, Variatza, & Balcazar, 2014). Mobile genetic elements like, plasmids, transposons, insertion sequences and integrons are the important factors for the occurrence of HGT. In a study carried out in lake Michigan, about 32%-100% were plasmid-associated ARGs among overal identified ARGs (Yang, et al., 2018). The presence of aquatic bacteria biofilms on the sediments, clay and epilation favors the HGT combined with the presence of bacteriophages. The aquaculture system is considered a hotspot for AMR genes, where significant genetic exchange and recombination takes place (Baquero, Martinez, & Canton, 2008). The process by which bacteria develop resistance against certain bactericidal vary greatly with species and this generally occurs at a genetic level. It was revealed that bacteria can transmit resistance genes through conjugation in which resistance genes are passed direct through cell contact via hollow tubes called pili (Shanks & Peteroy-Kelly, 2009). Bacteria also use a transformation process, in which foreign DNA is incorporated into their genome, to propagate resistance. Transduction is another mechanism through which resistance is developed, in this method genetic material is transfer via a viral vector (Courvalin, 1994). The presence of AMR in various aquatic environments has been detected and it has been found that some resistance determinants are originated from aquatic bacteria, such as plasmid-mediated quinolone resistance determinants from the qnr family and CTX-M from aquatic Kluyvera spp (Cantas, et al., 2013). It has been found that the presence of integrons plays an important role in the HGT of ARGs in the environment. Moreover, bioinformatic analysis which detects the transfer of mobile resistome in bacteria suggests that transfer depends on the bacterial community composition. Hence, the transfer of ARGs due to selection pressure in lakes depends on the development of a specific antibiotic resistance bacteria population and its transfer between various bacterial groups (Hu, Gao, & Zhu, 2017). About 90% of bacteria belonging to seawater are resistant to one or more antibiotics and up to 20% of the bacteria can resist at least five. After the development of the AMR gene bacteria can live up to several years in the environment even after cessation of selective pressure (Watts et al., 2017).
The numbers of antimicrobial agents used in aquaculture are identified as critically important for human medicine by World Health Organization. Hence, the occurrence of resistance to these antimicrobials in human pathogens possess a serious threat to human health and it limits the therapeutic options. That's why the use of these agents should be control to prevent the spread of drug resistance.